2-166288478-G-T

Position:

• chr2-166288478-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001365536.1(SCN9A):​c.1273C>A​(p.Gln425Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q425H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.23

Genes affected

SCN9A (HGNC:10597): (sodium voltage-gated channel alpha subunit 9) This gene encodes a voltage-gated sodium channel which plays a significant role in nociception signaling. Mutations in this gene have been associated with primary erythermalgia, channelopathy-associated insensitivity to pain, and paroxysmal extreme pain disorder. [provided by RefSeq, Aug 2009]

SCN1A-AS1 (HGNC:54069): (SCN1A and SCN9A antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35487252).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN9A	NM_001365536.1	c.1273C>A	p.Gln425Lys	missense_variant	10/27	ENST00000642356.2
SCN1A-AS1	NR_110260.1	n.1030-6087G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN9A	ENST00000642356.2	c.1273C>A	p.Gln425Lys	missense_variant	10/27		NM_001365536.1	P1
SCN1A-AS1	ENST00000651574.1	n.1708-6087G>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Generalized epilepsy with febrile seizures plus, type 7;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 28, 2020

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals with SCN9A-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamine with lysine at codon 425 of the SCN9A protein (p.Gln425Lys). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and lysine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	.;T;.;.;T;.;.
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.89	D;.;D;D;D;D;D
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.35	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.51	D
MutationAssessor	Benign	1.2	L;L;L;.;L;L;.
MutationTaster	Benign	0.89	N;N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.9	N;N;.;.;.;N;.
REVEL	Uncertain	0.39
Sift	Benign	0.038	D;T;.;.;.;D;.
Sift4G	Benign	0.47	T;T;.;.;.;T;.
Polyphen		0.89	.;P;.;.;P;.;.
Vest4		0.35
MVP		0.66
MPC		0.24
ClinPred		0.63	D
GERP RS		4.8
Varity_R		0.24
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1553491073; hg19: chr2-167144988;